The primate polyomaviruses include JCV and BKV, which infect humans, and the closely related SV40 of macaques. In immunocompetent hosts, primary infection occurs early in life, with mild or absent clinical signs. The virus then persists as a latent infection mainly in kidney. Reactivation with viral shedding can occur with pregnancy, chronic diseases or immunocompromise, and may or may not be associated with clinical signs. JCV is associated with progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS) due to infection of oligodendrocytes, in up to 5% of AIDS patients. BKV causes interstitial nephritis and/or hemorrhagic cystitis, particularly in transplant recipients. Similarly, SV40 is associated with both PML and nephritis in SIV-infected macaques with simian AIDS. Previous studies indicated that SV40 causes interstitial nephritis in primary infections, and PML upon reactivation of a latent infection in SIV-infected macaques. We now recognize a second CNS manifestation of SV40 a meningoencephalitis affecting cerebral gray matter, without demyelination, distinct from PML. This lesion can be a primary manifestation of SV40 in conjunction with SV40-induced interstitial nephritis. In situ hybridization for SV40, coupled with immunohistochemistry for glial fibrillary acidic protein on the same section, demonstrates that many of the infected cells in the meningoencephalitic lesions are astrocytes, in contrast to PML, where the majority of infected cells are oligodendrocytes. Preliminary sequence data on SV40 isolated from macaques with concurrent meningoencephalitis and renal disease suggest that these two lesions are caused by an identical strain of virus, which differs from that associated with PML.